FGF21 and its underlying adipose tissue-liver axis inform cardiometabolic burden and improvement in obesity after metabolic surgeryResearch in context
Marie Patt,
Isabel Karkossa,
Laura Krieg,
Lucas Massier,
Kassem Makki,
Shirin Tabei,
Thomas Karlas,
Arne Dietrich,
Martin Gericke,
Michael Stumvoll,
Matthias Blüher,
Martin von Bergen,
Kristin Schubert,
Peter Kovacs,
Rima M. Chakaroun
Affiliations
Marie Patt
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany
Isabel Karkossa
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
Laura Krieg
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
Lucas Massier
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
Kassem Makki
INSERM U1060, INRAE UMR1397, Université de Lyon, France
Shirin Tabei
Institute of Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany; Centre of Brain, Behaviour, and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
Thomas Karlas
Division of Gastroenterology, Medical Department II, University of Leipzig Medical Centre, Leipzig, Germany
Arne Dietrich
Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Centre, Leipzig, Germany
Martin Gericke
Leipzig University, Institute of Anatomy, Leipzig, Germany
Michael Stumvoll
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
Matthias Blüher
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
Martin von Bergen
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany; Institute of Biochemistry, Leipzig University, Leipzig, Germany; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
Kristin Schubert
Department of Molecular Systems Biology, Helmholtz-Centre for Environmental Research - UFZ, Leipzig, Germany
Peter Kovacs
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Deutsches Zentrum für Diabetesforschung e.V., 85764, Neuherberg, Germany
Rima M. Chakaroun
University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany; Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Centre for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, Sweden; Corresponding author. University of Leipzig Medical Centre, Medical Department III–Endocrinology, Nephrology, Rheumatology, Leipzig, Germany.
Summary: Background: This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery. Methods: We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes. Findings: FGF21 levels were linked to central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, and were driven by circulating leptin and liver enzymes. Higher FGF21 were linked with AT dysfunction reflected in fibro-inflammatory and lipid dysmetabolism pathways. Specifically, visceral AT inflammation was tied to both FGF21 elevation and liver dysfunction. Post-surgery, FGF21 peaked transitorily at three months. Mediation analysis highlighted an underlying increased AT catabolic state with elevated free fatty acids (FFA), contributing to higher liver stress and FGF21 levels (total effect of free fatty acids on FGF21 levels: 0.38, p < 0.01; proportion mediation via liver 32%, p < 0.01). In line with this, histological AT fibrosis linked with less pronounced FGF21 responses and reduced fat loss post-surgery (FFA and visceral AT fibrosis: rho = −0.31, p = 0.030; FFA and fat-mass loss: rho = 0.17, p = 0.020). Interpretation: FGF21 reflects the liver's disproportionate metabolic stress response in both central adiposity and after metabolic surgery, with its dynamics reflecting an AT-liver crosstalk. Funding: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838, CRC1382 and a Walther-Benjamin Fellowship and by a junior research grant by the Medical Faculty, University of Leipzig, and by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501. Part of this work was supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 and by the CRC1382 and the Novo Nordisk Foundation and by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project number 530364326.
